Aging is a phenomenon that appears as living organisms grow older and includes degradation in physiological functions of living bodies caused by a change in cells, genes or proteins. Skin aging begins gradually at an age of 17-25, when body growth is terminated. Even after skin aging begins, the epidermis is changed (regenerated) through the division of basal cells. However, the dermis does not grow any longer. Main factors causing such phenomena include loss of moisture in the skin accompanied by degradation in biosynthesis of intercellular substances resulting from intracellular inflammation. Therefore, in order to reduce wrinkles and prevent aging, it is required to maintain the skin in a moisturized state, to protect the skin from the external environment, and to inhibit inflammation in the skin.
Among several layers forming the skin, the epidermis is the most important layer that protects the body from the external environment and maintains the skin in an elastic and moisturized state. The epidermis functions to inhibit foreign materials from penetrating into the living body and to prevent loss of moisture inside the living body. Maintenance of an adequate amount of moisture is very important to maintain the skin elasticity and softness. Meanwhile, as skin aging proceeds, reduced secretion of sebum results in a lack of skin oil and degradation of the capability of preventing skin moisture evaporation, thereby causing drying of the epidermis and generation of fine wrinkles. In addition, when external irritation factors, such as sunlight, are applied continuously to the skin, keratinocytes generate various chemicals, such as cytokines, and the information thereof is transferred to the cells in the dermis, resulting in a change in the metabolism of fibroblasts. Further, when cytokines act on vascular endothelial cells, immune cells including lymphocytes secrete enzymes, such as collagenase or elastase, which decompose fibrous proteins, in blood vessels, thereby causing decomposition of collagen and elastin. As a result, there is generated an imbalance between the amount of newly synthesized fibrous proteins and the amount of decomposed fibrous proteins. When the process is repeated, skin elasticity is lowered and wrinkles or skin sagging phenomena occur. In addition to the above, as the human body undergoes aging, immune functions are lowered and the skin becomes dry and rough, so that the skin is susceptible to infection by bacteria and may suffer from a serious inflammation. Further, as the skin cornification cycle become longer, the horny layer grows thicker and rougher.
Inflammation is caused by the activation of inflammatory factors due to the oxidative stresses including ultraviolet rays (UV), reactive oxygen species, free radicals, etc., and results in various diseases and skin aging. One of the characteristics of inflammation is an increased in addition of oxygen to arachidonic acid metabolized via the cyclooxygenase (COX) pathway, by which prostaglandin is produced, and the 5-lipoxygenase pathway, by which leukotriene is produced. Both prostaglandin and leukotriene are mediators of inflammation. Therefore, therapeutic methods designed to inhibit activities of COX and/or lipoxygenase have been recently spotlighted. COXs are classified into two types: COX-1 and COX-2. It seems that the latter, i.e., COX-2, plays an important role in the progress of inflammation. Additionally, unlike the irreversible inhibition of COX-1, inhibition of COX-2 is effective for reducing inflammation without any related side effects.
Another strong inflammation mediator is nitric oxide (NO), which is produced from L-arginine by NO synthase (NOS), and is generated in many types of cells due to stresses, such as UV, endotoxin, cytokines, etc. Such inflammatory stimuli increase the expression of inducible NOS in cells to generate NO, and activate macrophages to cause inflammation.
Hyaluronic acids used herein are found in the placenta, eyes and joints of animals, the cockscomb, etc., and have been commercialized in the fields of medicines, cosmetics and foods. More recently, hyaluronic acids have been produced and used via a fermentation process using microorganisms, considering the possibility of infective diseases that may be derived from animals. Hyaluronic acids have a chain structure in which D-glucuronic acid and N-acetyl-D-glucosamine are linked via β-1,3 bonding repeatedly, wherein the repeating units are linked with each other via β-1,4 bonding. Hyaluronic acids are molecular clusters whose molecular weights range from hundreds of thousands to several millions of Daltons (Da), and have very high viscosity. Hyaluronic acids function to allow cells to be in contact with each other, to soften joints, or to bind or support the whole body, skin, organs or cells. Hyaluronic acids are found in substantially all parts of the human body, particularly in the subcutaneous fat layer, joint portions, synovial fluid, umbilical cords and the lenses of eye balls at a high amount. It is reported that hyaluronic acids participate in maintaining intercellular distances, cell division and differentiation, transfer, immune modulation, etc. It is also reported that the amount of hyaluronic acids in the human skin decreases as the aging proceeds. It is thought that such a decrease in hyaluronic acids is one of the direct causes of degradation of skin elasticity and a drop in moisture content. The inventors recently found that hyaluronic acids show different in vivo mechanisms and effects depending on their molecular weights. In brief, high-molecular weight hyaluronic acid functions to inhibit loss of skin moisture by forming a film on the skin. On the other hand, low-molecular weight hyaluronic acid penetrates into the cell layer, which is hardly penetrated by high-molecular weight hyaluronic acid, as much as 16.0%, as measured by the cell layer penetration test using Caco-2 cells. Additionally, low-molecular weight hyaluronic acid shows a permeability as high as about 90% in the skin permeation test using artificial skin. Further, through measurement of the skin moisture content and transdermal moisture loss, low-molecular weight hyaluronic acid is confirmed to have a high moisturizing effect comparable to that of high-molecular weight hyaluronic acid.
Ulmus davidiana is a deciduous broad-leaved tree belonging to the family Ulmaceae, the order Urticales, of the division Dicotyledon, and is also called spring elm or house elm. Ulmus davidiana is a deciduous arbor as tall as about 10 m. The leaves have a broad ellipsoidal shape and teeth. In spring, light green-colored small flowers blossom in a group. Ulmus davidiana is also called elm (), and the bark thereof is called elm bark () or white elm bark () and the root bark thereof is called elm root bark () in Chinese character. The bark contains flavonoids, saponins, tannins (3%) and a large amount of viscous materials. The root bark of Ulmus davidiana is used after the root bark is peeled around June and the outer shell is trimmed before drying under the sunlight. The extract of root bark from Ulmus davidiana is reported to have the effect of alleviating inflammation. In addition, the extract of Ulmus davidiana reinforces motions of the small intestine and the smooth muscle of bladder, and has cough-alleviating, astringenting and anti-inflammatory effects. In folk remedies, elm bark is boiled down so that it is taken for treating stomachaches or backaches. The other applications include an anti-inflammatory salve to be applied to festering wounds.